Novel benzyl-substituted N-heterocyclic carbene-silver acetate complexes: synthesis, cytotoxicity and antibacterial studies

Metallomics. 2011 Jan;3(1):74-88. doi: 10.1039/c0mt00034e. Epub 2010 Dec 6.

Abstract

From the reaction of 1-methylimidazole (1a), 4,5-dichloro-1H-imidazole (1b(I)) and 1-methylbenzimidazole (1c) with p-cyanobenzyl bromide (2a), non-symmetrically substituted N-heterocyclic carbene (NHC) [(3a-c)] precursors, 5,6-dimethyl-1H-benzimidazole (1d) and 4,5-diphenyl-1H-imidazole (1e) with p-cyanobenzyl bromide (2a) and benzyl bromide (2b), symmetrically substituted N-heterocyclic carbene (NHC) [(3d-f)] precursors were synthesised. These NHC-precursors were then reacted with silver(i) acetate to yield the NHC-silver complexes (1-methyl-3-(4-cyanobenzyl)imidazole-2-ylidene)silver(i)acetate (4a), (4,5-dichloro-1-(4-cyanobenzyl)-3-methyl)imidazole-2-ylidene)silver(i)acetate (4b), (1-methyl-3-(4-cyanobenzyl)benzimidazole-2-ylidene)silver(i)acetate (4c), (1,3-bis(4-cyanobenzyl)5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4d), (1,3-dibenzyl-5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4e) and (1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene) silver(i) acetate (4f) respectively. Three NHC-precursors 3c-e and four NHC-silver complexes 4b and 4d-f were characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial activity of the NHC-precursors and NHC-silver complexes was investigated against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative Kirby-Bauer disk-diffusion method. NHC-silver complexes have shown very high antibacterial activity compared to the NHC-precursors. All six NHC-silver complexes were tested for their cytotoxicity through MTT based in vitro tests on the human renal-cancer cell line Caki-1 in order to determine their IC₅₀ values. NHC-silver complexes 4a-f were found to have IC₅₀ values of 6.2 (±1.0), 7.7 (±1.6), 1.2 (±0.6), 10.8 (±1.9), 24.2 (±1.8) and 13.6 (±1.0) μM, respectively. These values represent improved cytotoxicity against Caki-1, most notably for 4c, which is a three times more cytotoxic than cisplatin (IC₅₀ value = 3.3 μM) itself.

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry
  • Acetates / pharmacology
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Benzyl Compounds / chemical synthesis
  • Benzyl Compounds / chemistry*
  • Benzyl Compounds / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Escherichia coli / drug effects
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Imidazoles / chemistry
  • Methane / analogs & derivatives*
  • Methane / chemical synthesis
  • Methane / chemistry
  • Methane / pharmacology
  • Microbial Sensitivity Tests
  • Silver Compounds / chemical synthesis
  • Silver Compounds / chemistry
  • Silver Compounds / pharmacology
  • Staphylococcus aureus / drug effects
  • X-Ray Diffraction

Substances

  • Acetates
  • Anti-Bacterial Agents
  • Benzyl Compounds
  • Heterocyclic Compounds
  • Imidazoles
  • Silver Compounds
  • silver acetate
  • carbene
  • Methane